Breast Cancer Research and Treatment

, Volume 85, Issue 2, pp 103–110 | Cite as

Naringenin Inhibits Glucose Uptake in MCF-7 Breast Cancer Cells: A Mechanism for Impaired Cellular Proliferation

  • Anne W. Harmon
  • Yashomati M. PatelEmail author


Certain flavonoids inhibit glucose uptake in cultured cells. In this report, we show that the grapefruit flavanone naringenin inhibited insulin-stimulated glucose uptake in proliferating and growth-arrested MCF-7 breast cancer cells. Our findings indicate that naringenin inhibits the activity of phosphoinositide 3-kinase (PI3K), a key regulator of insulin-induced GLUT4 translocation, as shown by impaired phosphorylation of the downstream signaling molecule Akt. Naringenin also inhibited the phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK). Inhibition of the MAPK pathway with PD98059, a MAPK kinase inhibitor, reduced insulin-stimulated glucose uptake by approximately 60%. The MAPK pathway therefore appears to contribute significantly to insulin-stimulated glucose uptake in breast cancer cells. Importantly, decreasing the availability of glucose by lowering the glucose concentration of the culture medium inhibited proliferation, as did treatment with naringenin. Collectively, our findings suggest that naringenin inhibits the proliferation of MCF-7 cells via impaired glucose uptake. Because a physiologically attainable dose of 10 µM naringenin reduced insulin-stimulated glucose uptake by nearly 25% and also reduced cell proliferation, naringenin may possess therapeutic potential as an anti-proliferative agent.

Akt breast cancer grapefruit mitogen-activated protein kinase phosphoinositide 3-kinase 


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  1. 1.
    Younes M, Brown RW, Mody DR, Fernandez L, Laucirica R: GLUT1 expression in human breast carcinoma: correlation with known prognostic markers. Anticancer Res 15: 2895–2898, 1995Google Scholar
  2. 2.
    Younes M, Lechago LV, Somoano JR, Mosharaf M, Lechago J: Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers. Cancer Res 56: 1164–1167, 1996Google Scholar
  3. 3.
    Brown RS, Wahl RL: Overexpression of Glut-1 glucose transporter in human breast cancer: an immunohistochemical study. Cancer 72: 2979–2985, 1993Google Scholar
  4. 4.
    Binder C, Binder L, Marx D, Schauer A, Hiddemann W: Deregulated simultaneous expression of multiple glucose transporter isoforms in malignant cells and tissues. Anticancer Res 17: 4299–4304, 1997Google Scholar
  5. 5.
    Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR: Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14: 4902–4911, 1994Google Scholar
  6. 6.
    Tanti JF, Gremeaux T, Grillo S, Calleja V, Klippe A, Williams LT, Van Obberghen E, Le Marchand-Brustel Y: Overexpression of a constitutively active form of phosphatidylinositol 3-kinase is sufficient to promote Glut 4 translocation in adipocytes. J Biol Chem 271: 25227–25232, 1996Google Scholar
  7. 7.
    Resh MD: Development of insulin responsiveness of the glucose transporter and the (Na+,K+)-adenosine triphosphatase during in vitro adipocyte differentiation. J Biol Chem 257: 6978–6986, 1982Google Scholar
  8. 8.
    Singh A, Purohit A, Hejaz HAM, Potter BVL, Reed MJ: Inhibition of deoxyglucose uptake in MCF-7 breast cancer cells by 2-methoxyestrone and 2-methoxyestrone-3-O-sulfamate. Mol Cell Endocrinol 160: 61–66, 2000Google Scholar
  9. 9.
    Noguchi Y, Sato S, Marat D, Doi C, Yoshikawa T, Saito A, Ito T, Tsuburaya A, Yanuma S: Glucose uptake in the human gastric cancer cell line, MKN28, is increased by insulin stimulation. Cancer Lett 140: 69–74, 1999Google Scholar
  10. 10.
    Yamamoto M, Patel NA, Taggart J, Sridhar R, Cooper DR: A shift from normal to high glucose levels stimulates cell proliferation in drug sensitive MCF-7 breast cancer cells but not in multidrug resistant MCF-7/ADR cells which overproduce PKC-βII. Int J Cancer 83: 98–106, 1999Google Scholar
  11. 11.
    Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, Cooper DR, Yasuda K: Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-α and PPAR expression. Biochim Biophys Acta 1592: 107–116, 2002Google Scholar
  12. 12.
    Park JB: Flavonoids are potential inhibitors of glucose uptake in U937 cells. Biochem Biophys Res Commun 260: 568–574, 1999Google Scholar
  13. 13.
    Harmon AW, Patel YP: Naringenin inhibits phosphoinositide 3-kinase activity and glucose uptake in 3T3-L1 adipocytes. Biochem Biophys Res Commun 305: 229–234, 2003Google Scholar
  14. 14.
    Kanzaki M, Pessin JE: Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. J Biol Chem 276: 42436–42444, 2001Google Scholar
  15. 15.
    Marrero MB, Schieffer B, Li B, Sun J, Harp JB, Ling BN: Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II-and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. J Biol Chem 272: 24684–24690, 1997Google Scholar
  16. 16.
    Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685, 1970Google Scholar
  17. 17.
    Maestro B, Campion J, Davila N, Calle C: Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J 47: 383–391, 2000Google Scholar
  18. 18.
    Rivenzon-Segal D, Rushkin E, Polak-Charcon S, Degani H: Glucose transporters and transport kinetics in retinoic acid-differentiated T47D human breast cancer cells. Am J Physiol 279: E508–E519, 2000Google Scholar
  19. 19.
    Zamora-León SP, Golde DW, Concha II, Rivas CI, Delgado-López F, Baselga J, Nualart F, Vera JC: Expression of the fructose transporter GLUT5 in human breast cancer. Proc Natl Acad Sci USA 93: 1847–1852, 1996Google Scholar
  20. 20.
    Baumann CA, Saltiel AR: Spatial compartmentalization of signal transduction in insulin action. Bioessays 23: 215–222, 2001Google Scholar
  21. 21.
    Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA: Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541–6551, 1996Google Scholar
  22. 22.
    Avruch J, Khokhlatchev A, Kyriakis JM, Luo Z, Tzivion G, Vavvas D, Zhang XF: Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res 56: 127–155, 2001Google Scholar
  23. 23.
    Hoffman BD, Hanauske-Abel HM, Flint A, Lalande M: A new class of reversible cell cycle inhibitors. Cytometry 12: 26–32, 1991Google Scholar
  24. 24.
    Erlund I, Meririnne E, Alfthan G, Aro A: Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J Nutr 131: 235–241, 2001Google Scholar
  25. 25.
    Lazar DF, Wiese RJ, Brady MJ, Mastick CC, Waters SB, Yamauchi K, Pessin JE, Cuatrecasas P, Saltiel AR: Mitogenactivated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem 270: 20801–20807, 1995Google Scholar
  26. 26.
    Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR: A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92: 7686–7689, 1995Google Scholar
  27. 27.
    Prusty D, Park BH, Davis KE, Farmer SR: Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor (PPAR) and C/EBP gene expression during the differentiation of 3T3-L1 preadipocytes. J Biol Chem 277: 46226–46232, 2002Google Scholar
  28. 28.
    Tang QQ, Otto TC, Lane MD: Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc Natl Acad Sci USA 100: 44–49, 2003Google Scholar
  29. 29.
    Culbert AA, Tavare JM: Multiple signalling pathways mediate insulin-stimulated gene expression in 3T3-L1 adipocytes. Biochim Biophys Acta 1578: 43–50, 2002Google Scholar
  30. 30.
    Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM: Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273: 18623–18632, 1998Google Scholar
  31. 31.
    Kamanna VS, Bassa BV, Vaziri ND, Roh DD: Atherogenic lipoproteins and tyrosine kinase mitogenic signaling in mesangial cells. Kidney Int Suppl 71: S70–S75, 1999Google Scholar
  32. 32.
    Tarnawski AS, Jones MK: The role of epidermal growth factor (EGF) and its receptor in mucosal protection, adaptation to injury, and ulcer healing: involvement of EGF-R signal transduction pathways. J Clin Gastroenterol 27(Suppl 1): S12–S20, 1998Google Scholar
  33. 33.
    Boney CM, Smith RM, Gruppuso PA: Modulation of insulinlike growth factor I mitogenic signaling in 3T3-L1 preadipocyte differentiation. Endocrinology 139: 1638–1644, 1998Google Scholar
  34. 34.
    Bornfeldt KE, Campbell JS, Koyama H, Argast GM, Leslie CC, Raines EW, Krebs EG, Ross R: The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells: dependence on the availability of downstream targets. J Clin Invest 100: 875–885, 1997Google Scholar
  35. 35.
    Lopez-Ilasaca M: Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol 56: 269–277, 1998Google Scholar
  36. 36.
    Kerkhoff E, Rapp UR: Cell cycle targets of Ras/Raf signaling. Oncogene 17: 1457–1462, 1998Google Scholar
  37. 37.
    So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK: Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 26: 167–181, 1996Google Scholar
  38. 38.
    Bhagwat S, Beecher GR, Haytowitz DB, Holden JM, Gebhardt S, Dwyer J, Peterson J, Eldridge A: Development of a database for flavonoids in foods. fnic/foodcomp/Data/Other/NDBC26_Flav.pdf, 2002, accessed on 27 March 2003Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.Department of NutritionUniversity of North Carolina School of Public HealthChapel HillUSA

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